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. 2022 Mar 9;28:e934588-1–e934588-24. doi: 10.12659/MSM.934588

Prognostic Significance of Clinicopathological Factors Influencing Overall Survival and Event-Free Survival of Patients with Cervical Cancer: A Systematic Review and Meta-Analysis

Shengwei Kang 1,2,B,D,E, Junxiang Wu 2,C, Jie Li 2,F, Qing Hou 1,D,E,F, Bin Tang 2,A,G,✉
PMCID: PMC8919681  PMID: 35260545

Abstract

Background

Cervical cancer (CC) is the most frequent type of cancer among women and its poor prognosis is a main concern, while the prognostic factors for CC have still remained controversial. We conducted this systematic review and meta-analysis to identify the prognostic significance of clinicopathological factors, influencing overall survival (OS), and event-free survival (EFS) of CC patients.

Material/Methods

The electronic databases of PubMed, EmBase, and the Cochrane library were systematically searched for identification of eligible studies published until June 2021. The pooled hazard ratio (HR) with 95% confidence interval (CI) were calculated using the random-effects model. Sensitivity and subgroup analyses and assessment of publication bias were also conducted.

Results

We selected 140 studies that involved 47 965 patients for the meta-analysis. The results revealed that age, cell type, depth of tumor invasion, the International Federation of Gynecology and Obstetrics stage, hemoglobin level, histological grade, leukocytosis, lymph node involvement, lymph-vascular space invasion, neutrophil-to-lymphocyte ratio, parametrial invasion, platelet-to-lymphocyte ratio, resection margin, squamous cell carcinoma antigen level, thrombocytosis, tumor grade, tumor size, and tumor volume were clinicopathological factors influencing OS and EFS of CC patients (P<0.05).

Conclusions

This study comprehensively identified the prognostic significance of clinicopathological factors, influencing OS, and EFS of CC patients. However, further large-scale prospective studies should be conducted to verify our findings and develop more accurate prognostic models for CC.

Keywords: Pathological Conditions, Signs and Symptoms; Prognosis; Uterine Cervical Neoplasms

Background

Cervical cancer (CC) is a frequent gynecologic malignancy and is the primary cause of cancer-related deaths in women worldwide [1,2]. A total of 604 127 new cases and 341 831 CC-related deaths were reported in 2020, accounting for 7.7% of all cancer-related deaths in women [1]. The HPV infection rate is rising, particularly in developing countries, where the incidence and prevalence of CC are still high, which can be attributed to the lack of a universal and integrated vaccination program for CC [3,4]. The prognosis of CC could be improved by a variety of treatment strategies on the basis of the disease stage, metastasis, or recurrence [2,5]. The International Federation of Gynecology and Obstetrics (FIGO) staging system has been widely used for predicting the prognosis of CC patients, while the prognosis of CC patients with the same FIGO stage varies [6]. Several prognostic models have already been introduced to predict the prognosis of CC on the basis of tumor and demographic characteristics [7–10], but the practicality of these models is limited by uneven quality and various characteristics of clinical setting, outcomes, and predictors. Therefore, additional prognostic factors should be explored to improve the prognosis of CC patients.

We therefore attempted to construct a prognostic model using the previously defined factors to predict the prognosis of CC patients. Numerous systematic reviews and meta-analyses have been performed to identify the prognostic significance of other variables in estimating the rates of overall survival (OS) and event-free survival (EFS) [11–15]. However, the other clinicopathological characteristics influencing the prognosis of CC patients were not assessed. There is an urgent need to summarize the prognostic variables to establish more comprehensive prognostic models. We therefore conducted the present systematic review and meta-analysis to identify the prognostic factors for CC and we also investigated the prognostic significance of these factors for CC.

Material and Methods

Search Strategy and Selection Criteria

The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement was utilized, as described previously [16]. Studies on the prognostic significance of clinicopathological factors, influencing OS, and EFS of CC patients were selected, and the language was restricted to English. No restriction was placed on publication status, including published, in press, or in progress. The electronic databases of PubMed, EmBase, and the Cochrane library were systematically searched for retrieving potential studies published until June 2021 using the following text word or Medical Subject Heading terms: (“cervical cancer” OR “cervical carcinoma” OR “cervical intraepithelial neoplasia” OR “uterine cervix cancer”) AND (“prognosis” OR “prognostic” OR “survival” OR “recurrence”). We also manually searched the reference lists of relevant reviews and original articles to identify eligible studies.

The literature search and study selection were independently performed by 2 reviewers, and the inconsistencies between reviewers were resolved by group discussion until a consensus could be reached. The following inclusion criteria were considered: (1) Study design: prospective or retrospective studies; (2) Patients: all patients who were diagnosed with CC; (3) Exposure: the clinicopathological factors reported ≥3 studies, including patients’ age, cell type, depth of tumor invasion, FIGO stage, hemoglobin level, histological grade, leukocytosis, lymph node involvement (LNI), lymph-vascular space invasion (LVSI), neutrophil-to-lymphocyte ratio (NLR), parametrial invasion, platelet-to-lymphocyte ratio (PLR), resection margin, squamous cell carcinoma antigen (SCCA), thrombocytosis, tumor grade, tumor size, and tumor volume; and (4) Clinical outcomes: OS or EFS. Reviews and abstracts were excluded because they contain no original data or have an unclear definition of prognostic factors.

Data Collection and Quality Assessment

Two reviewers independently abstracted the following items: characteristics of studies (the first author’s full name, year of publication, the first author’s country of residence, and study design), sample size, mean or median age, FIGO stage, follow-up duration, clinical outcomes, and prognostic factors. Then, these 2 reviewers assessed the quality of each study using the Newcastle-Ottawa Scale (NOS) score, which ranges from 0–9 stars for assessment of quality of each study [17]. Studies were classified into low quality (0–6 stars), medium quality (7–8 stars), and high quality (9 stars). Any disagreement between reviewers for data collection and quality assessment was resolved via reading the full-text of the included studies by the third reviewer.

Statistical Analysis

The prognostic factors, influencing OS and EFS of CC patients were presented as hazard ratio (HR) and 95% confidence interval (CI) for each individual study, and the pooled HRs and 95% CIs were calculated using the random-effects model, as described elsewhere [18,19]. Heterogeneity among the included studies was assessed using the Cochran’s Q-statistic and the I2-statistic, and a significant heterogeneity was defined as I2 ≥50.0% or P<0.10 [20,21]. To determine sources of heterogeneity, we performed a leave-one-out sensitivity analysis via exclusion of individual studies one at a time, and the pooled estimates were recalculated for the remaining studies [22]. Subgroup analyses were undertaken on the basis of the first author’s country of residence, FIGO stage, cutoff value, and study quality, and the subgroups were calculated using the chi-square test to explore the differences in the estimates between subgroups [23]. The Eastern countries contained Asia, while Western countries including Europe, America, and Oceania. Assessment of publication bias was carried out by using Egger’s and Begg’s tests, which compared the summary estimate of each study to its precision for outcomes that were reported in more than 5 studies [24,25]. The trim and fill method was applied to adjust pooled results if significant publication bias was observed [26]. Two-sided P<0.05 was regarded as statistically significant. The STATA 10.0 software was used to conduct the statistical analyses (Stata Corporation, College Station, TX, USA).

Results

Literature Search

The search strategy resulted in retrieving 18 912 articles, and 9141 articles were retained after exclusion of 9771 studies owning to duplicate publication. Then, 8762 studies were excluded because of irrelevant titles, the review of the reference lists of potentially relevant studies indicated 21 studies, and a total of 380 studies were retrieved for further full-text evaluations. Next, 240 studies were removed because they investigated other interventions (n=169), had inadequate outcomes (n=46), and were review articles (n=25). The remaining 140 studies were selected for the final meta-analysis (Figure 1), and characteristics of the eligible studies are presented in Table 1 [27–166].

Figure 1.

Figure 1

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The PRISMA flowchart for the literature search and the study selection.

Table 1.

The baseline characteristics of included studies.

Study Country Study design Sample size Age (years) FIGO stage Follow-up (years) Reported outcomes Prognostic factors NOS score
Sevin 1995 [27] USA Retro 301 43.5 I–II 5.0 DFS DI, TS, LVSI, LNI, TV, FIGO, RM, CT, TG, age 6
Werner-Wasik 1995 [28] USA Retro 125 55.0 I–II 5.0 DFS LNI, LVSI, PI, He, TS, FIGO, CT, TG 5
Tsai 1999 [29] China Retro 222 50.0 I–II 5.0 DFS FIGO, TS, age, CT, SCC, He, LNI, PI, LVSI, RM 6
Lai 1999 [30] China Retro 891 NA I–II 5.0 DFS TG, FIGO, TS,DI 7
Nakanishi 2000 [31] Japan Retro 509 49.3 I 9.3 OS, DFS CT, LNI, and TS 6
Hernandez 2000 [32] USA Retro 291 49.7 II–IV 5.0 PFS Th, LNI, TS, age, and FIGO 7
Alfsen 2001 [33] Norway Retro 505 53.0 I–IV 5.0 OS CT, LVSI, LNI, and age 7
Flores-Luna 2001 [34] Mexico Retro 378 52.2 I–IV 12.5 OS FIGO, TG, TS, and age 5
Trattner 2001 [35] Austria Retro 113 46.1 I–II 4.7 OS TV, LNI, LVSI, FIGO, PI, RM, CT, TG, and age 5
Yanoh 2001 [36] Japan Retro 751 45.0 I > 5.0 DFS LNI, PI, TS, DI, and LVSI 6
Takeda 2002 [37] Japan Retro 187 48.2 I–II 6.9 OS FIGO, CT, LVSI, TS, DI, PI, and LNI 6
Gasinska 2002 [38] Poland Retro 152 55.0 I–III 2.2 OS Age, TG, and He 6
Martin-Loeches 2002 [39] Spain Retro 114 49.1 I–II 10.0 OS TS, TV, DI 5
Brun 2003 [40] France Retro 308 53.0 I–IV 7.8 OS Age, TG, and PI 6
Morice 2003 [41] France Retro 193 37.0 I–II 5.0 OS FIGO, TS, LVSI, and LNI 6
Kodaira 2003 [42] Japan Retro 164 68.0 II–III 1.9 DFS TV, LNI, and FIGO 6
Grisaru 2003 [43] Canada Pro 871 42.1 I 4.1 DFS LNI, TG, LVSI, RM, and CT 7
Huang 2003 [44] China Pro 157 44.0 I–II 5.0 OS, DFS TS, age, CT 6
Shinohara 2004 [45] Japan Retro 130 49.0 I–II 14.4 DFS LVSI, LNI, and DI 6
Ho 2004 [46] China Retro 197 47.4 I–II 5.8 OS, DFS Age, FIGO, CT, TG, TS, DI, LVSI, LNI, PI 5
Ayhan 2004 [47] Turkey Retro 393 48.5 I 2.6 OS, DFS TS, LVSI, PI, 6
Choi 2006 [48] Korea Retro 85 50.0 I–IV 3.0 OS, DFS Age, CT, FIGO, TS, LNI, SCC, and He 5
Chittithaworn 2007 [49] Thailand Retro 205 44.2 I 4.7 DFS DI, LVSI, RM, and LNI 5
Grigiene 2007 [50] Lithuania Retro 162 52.0 II–III 2.7 OS, DFS FIGO, He 7
Horn 2007 [51] Germany Retro 245 43.0 II 4.5 OS TS, LNI, FIGO 6
Atahan 2007 [52] Turkey Retro 183 54.0 I–III 3.8 OS, DFS Age, PI, FIGO, TS, CT, LNI 7
Garcia-Arias 2007 [53] Mexico Retro 294 49.4 I–IV 2.3 OS Le, He, age, CT, and FIGO 7
Choi 2008 [54] Korea Retro 143 58.0 I–IV 2.2 PFS FIGO, TS 6
Behtash 2009 [55] Iran Retro 203 49.8 I–II 3.5 OS, DFS Age, CT, FIGO, TS, LNI, PI, LVSI, DI 6
Jacobson 2009 [56] USA Retro 436 52.3 I–IV 8.0 OS FIGO, CT 7
Zusterzeel 2009 [57] Netherlands Retro 167 42.0 I–IV 2.8 OS, DFS FIGO, CT, TG, LVSI, DI, TS 7
Polterauer 2010 [58] Austria Retro 88 49.9 I–IV 3.1 OS, DFS FIGO, TG, CT 7
Munagala 2010 [59] India Retro 89 46.0 I–III 5.0–7.0 OS, DFS/PFS Age, FIGO, LNI, PI, CT, TG, and TS 6
Huang 2010 [60] China Retro 960 45.0 I–II 5.0 OS FIGO,SCC, DI, PI 6
Touboul 2010 [61] France Retro 150 47.0 I–IV 3.6 OS FIGO, CT, RM, LNI 7
Horn 2010 [62] Germany Retro 194 44.0 I–II 5.1 OS LNI, TG, FIGO 6
Kodama 2010 [63] Japan Retro 97 46.0 I–II 8.4 OS, DFS Age, FIGO, DI, TS, PI, LVSI, LNI 5
Lee 2010 [64] Korea Retro 134 58.0 II–IV 3.2 OS, PFS FIGO 5
Tseng 2010 [65] China Pro 251 48.6 II–IV 6.3 OS SCC, TS, PI, LNI 6
Nugent 2010 [66] USA Retro 111 51.0 I–IV 1.4 OS, PFS FIGO 6
Srisomboon 2011 [67] Thailand Retro 680 44.5 I 4.0 DFS LNI, LVSI, CT, DI, PI, TG, RM 6
Seamon 2011 [68] USA Retro 381 47.0 I–IV 3.3 OS, DFS FIGO, CT, TG 7
Polterauer 2011 [69] Austria Retro 178 49.2 I–IV 3.8 OS, DFS FIGO, LNI, TG, age, CT 7
Mabuchi 2011 [70] Japan Retro/Pro 536 57.5 I–IV 6.4 OS, PFS Age, FIGO, CT, TS 6
Min 2011 [71] China Retro 88 NA I–II 5.0 OS Age, TS, CT, TG, FIGO, LNI 5
Biewenga 2011 [72] Netherlands Retro 710 41.0 I–II 5.2 DFS CT, TG, DI, PI, LNI, LVSI, RM 7
Polterauer 2012 [73] Austria Retro 528 47.9 I–IV 3.8 OS Age, FIGO, TS, CT, LNI, PI 7
Kim 2012 [74] Korea Retro 174 NA I–IV 2.5 OS, PFS FIGO, LNI, TS 6
Lee 2012 [75] Korea Retro 1,061 50.0 I–IV 4.4 OS, PFS NLR, FIGO, CT 7
Okazawa 2012 [76] Japan Retro 311 51.0 I–II 5.2 PFS Age, CT, LNI, PI, RM, DI, LVSI, TS, He 7
Wang 2012 [77] China Retro 179 47.0 I–IV 4.3 OS, DFS FIGO, LNI, RM 6
Yan 2012 [78] China Retro 148 42.0 I 2.3 OS Age, CT, TG, TS, DI, LVSI, LNI 5
Cibula 2012 [79] Czech Republic Retro 645 46.0 I–II 3.3 OS, DFS Age, FIGO, PI, LNI 6
Singh 2012 [80] Australia Retro 196 NA I–II 6.1 OS, DFS Age, LVSI, LNI, PI, TS, DI 7
Wang 2013 [81] China Retro 424 NA I–II 7.0 DFS Age, CT, TG, FIGO, LNI 5
Tsubamoto 2013 [82] Japan Retro 73 47.0 I–II 5.9 OS, DFS Age, FIGO, CT, TS, LNI 6
Song 2013 [83] Korea Retro 268 57.0 I–IV 5.0 OS, DFS FIGO, age, LNI, CT, He 6
Cho 2013 [84] Korea Retro 185 50.0 I–II 5.9 DFS Age, FIGO, LNI, RM, PI, TS, DI, LVSI 6
Zhang 2014 [85] China Retro 460 44.0 I–II 5.8 OS, PFS FIGO, LNI, NLR 7
Horn 2014 [86] Germany Retro 366 40.0 I 7.8 OS, DFS TS, LNI, TG 7
Noh 2014 [87] Korea Retro 1,323 50.0 I–II 6.3 OS, DFS CT, age, FIGO, TS, LNI, PI, LVSI, DI, RM 7
Yu 2014 [88] China Retro 153 NA II 5.0 DFS TS, LVSI, LNI 6
Liu 2014 [89] China Retro 184 46.0 I–II 5.8 OS, DFS Age, TS, CT, TG, FIGO, DI, LVSI, LNI 6
Kawano 2015 [90] Japan Retro 286 63.6 I–IV 6.7 OS Age, FIGO, PNI, CT, TS, He, Th 7
Ruengkhachorn 2015 [91] Thailand Retro 331 48.6 I–II 7.0 DFS He, CT, FIGO, PNI, PI, RM, DI, LVSI 6
Bradbury 2015 [92] UK Retro 92 39.5 I 4.8 OS, PFS Age, TS, CT, TG, LVSI, LNI, RM 7
Yuan 2015 [93] China Retro 38 40.4 I–II 5.0 OS, DFS PI 6
Mizunuma 2015 [94] Japan Retro 56 65.1 I–IV 6.7 OS, PFS FIGO, TS, He, NLR 6
Endo 2015 [95] Japan Retro 84 62.0 I–IV 6.7 OS Age, CT, He, TS, LNI 6
Zhao 2015 [96] China Retro 220 NA I–II 5.0 OS, DFS Age, FIGO, TG, CT, DI, TS, LNI 7
Takatori 2015 [97] Japan Retro 33 42.0 I–II 2.8 OS Age, FIGO, TS, SCC 5
Huang 2016 [98] China Retro 643 NA I–II 3.1 OS, DFS Age, CT, TG, TS, FIGO, DI, LVSI, LNI, PI, RM 7
Li 2016 [99] China Retro 347 51.6 I–II 3.1 OS, DFS Age, CT, FIGO, TG, DI, LVSI, RM, LNI, PI, SCCA 7
Cho 2016 [100] Korea Retro 2,456 56.0 I–IV 5.4 OS, DFS Age, FIGO, CT, TS, LNI, He, Le, NLR 7
Matsumiya 2016 [101] Japan Retro 54 55.0 I–IV 1.0 OS CT 6
Usami 2016 [102] Japan Retro 111 51.0 I–IV 1.4 OS Age, CT 6
Chen 2016 [103] China Retro 407 44.0 I–II 5.0 OS, DFS Age, CT, TG, DI, LVSI, LNI, FIGO, PI, PLR, NLR 6
Oishi 2016 [104] Japan Retro 85 55.0 IV 0.8 OS Age, CT, TS, TG, He, SCC 5
Onal 2016 [105] Turkey Retro 235 57.0 I–IV 5.8 OS, PFS Age, FIGO, TS, LNI, NLR 7
Wu 2016 [106] USA Retro 71 49.0 I–IV 2.1 OS, PFS FIGO, CT, TG 6
Xia 2016 [107] China Retro 274 43.0 I–II 2.4 OS, DFS Age, FIGO, CT, TS, TG, DI, LVSI, RM, PI, LNI 6
Lee 2017 [108] Korea Retro 231 58.0 I–IV 2.3 OS, PFS Age, LNI, FIGO, SCC, TV 7
Barquet-Muñoz 2017 [109] Mexico Retro 202 49.5 I–II 5.0 OS, DFS Age, CT, TS, DI, LVSI, RM, PI, LNI 6
Jung 2017 [110] Korea Retro 1,113 48.7 I–II 7.6 OS, DFS CT, FIGO, TS, DI, LNI, LVSI, PI, RM 7
Chung 2017 [111] Korea Retro 103 48.0 I–II 2.4 PFS FIGO, TS, LNI, PI, DI, LVSI 5
Zheng 2017 [112] China Retro 795 49.5 I–II 5.2 OS FIGO, He, TG, LVSI, LNI, TS, PI, RM 6
Obrzut 2017 [113] Poland Pro 102 48.0 I–II 10.0 OS, DFS FIGO, CT, TG, LNI, LVSI, RM 6
Cho 2017 [114] Korea Retro 105 NA II 4.8 PFS Age, CT, TS, LNI, NLR 5
Chandeying 2017 [115] Thailand Retro 626 45.0 I 7.7 OS, DFS CT, age, TS, FIGO, RM, PI, LNI, LVSI, DI 7
Yokoi 2017 [116] Japan Retro 249 61.5 II–IV 5.0 PFS Age, FIGO, LNI, CT, He 7
Lim 2017 [117] Korea Retro 180 NA I–II 5.0 OS, DFS PI, LNI 5
Xu 2018 [118] China Retro 40 45.5 I–IV 5.0 OS Age, FIGO, LNI, LVSI, DI, TS 6
Wen 2018 [119] China Retro 99 NA II–IV 4.0 DFS Age, TS, CT, FIGO, SCC, PI 6
Joo 2018 [120] Korea Retro 397 45.0 I–II 4.0 OS, DFS CT, FIGO, LNI, PI, LVSI, DI, TS 6
Dai 2018 [121] China Retro 302 45.1 I–II 5.0 OS FIGO, TS, TG, DI, LVSI, PI, LNI 6
Zhu 2018 [122] China Retro 365 45.0 I–II 3.7 OS, PFS Age, DI, LNI, LVSI, PI 5
Zhou 2018 [123] China Retro 312 46.0 I–II 4.7 OS, DFS Age, FIGO, TS, TG, DI, LVSI, LNI 5
Liu 2018 [124] China Retro 98 52.0 I–III 3.1 OS, PFS TS, LNI 5
Xie 2018 [125] China Retro 810 46.3 I–II 5.0 OS FIGO, LNI 5
Taarnhøj 2018 [126] Denmark Retro 1,523 NA I 5.0 DFS FIGO, CT, age, DI, LVSI 6
Zhang 2018 [127] China Retro 235 46.0 I–II 6.4 OS, PFS Age, FIGO, TS, CT, LVSI, LNI, DI, NLR 7
Je 2018 [128] Korea Retro 1,069 49.0 I–II 5.0 DFS CT, PI, LVSI, DI, TS, LNI 7
Ishikawa 2018 [129] Japan Retro 93 NA I–II 10.0 OS, DFS CT, TS, DI, LVSI, PI, LNI, RM 6
Kwon 2018 [130] Korea Retro 259 47.0 I–II 5.8 DFS CT, LVSI 6
Zhu 2019 [131] China Retro 110 51.5 I–II 4.0 OS, PFS Age, TS, LNI, FIGO, TG, Ly 6
Yan 2019 [132] China Retro 347 NA I–II 3.3 OS, PFS Age, FIGO, LNI, TG, LVSI, DI 6
Wang 2019 [133] China Retro 559 51.0 I–IV 3.3 DFS Age, SCC, FIGO, TS, LNI 7
Farzaneh 2019 [134] Iran Retro 307 40.4 I–III 5.0 DFS RM, NLR 5
Sawada 2019 [135] Japan Retro 107 46.0 I–II 4.8 OS FIGO, CT, TS, LNI, PI 6
Khalkhali 2019 [136] Iran Retro 109 50.1 I–IV 3.2 OS Age, FIGO 5
Yildirim 2019 [137] Turkey Retro 104 56.0 I–IV 4.4 OS, DFS TS, FIGO, LNI 6
Gai 2019 [138] China Retro 79 51.0 I–IV 5.0 OS FIGO, LNI, LVSI 6
Chen 2019 [139] China Retro 88 48.0 I–II 2.2 DFS Age, CT, FIGO, TG, LVSI 5
Guani 2019 [140] France Pro 139 NA I 3.0 DFS LNI, CT, TS, FIGO, LVSI, age 5
Huang 2019 [141] China Retro 458 45.0 I–II 3.9 OS Age, TG, TS, LNI, LVSI, FIGO, NLR 7
Queiroz 2019 [142] Brazil Retro 127 50.8 II–IV 4.1 OS, DFS Age, CT, TS, LNI 5
Gillani 2019 [143] Malaysia Pro 3,797 57.3 I–II 6.1 OS Age, FIGO, TS, LNI, CT 6
de Foucher 2019 [144] France Retro 501 54.0 I–II 3.0 OS, DFS FIGO, LNI 6
Yoshino 2019 [145] Japan Retro 128 65.0 I–IV 2.5 OS FIGO, CT 6
Zhang 2019 [146] China Retro 89 40.5 I–IV 4.8 OS FIGO, TS, LNI, LVSI, DI 6
Seebacher 2019 [147] Austria Retro 116 52.1 I–IV 1.7 OS Age, FIGO, CT, SCC 5
Holub 2019 [148] Spain Retro 151 52.8 I–IV 3.7 OS TS, FIGO, age, NLR 6
Theplib 2020 [149] Thailand Retro 196 41.0 I 5.0 OS, DFS LVSI, PI, LNI, DI 6
Maulard 2020 [150] France Pro 238 45.9 I–IV 4.4 OS FIGO, CT, LNI 7
An 2020 [151] China Retro 278 45.5 I–II 5.0 OS, DFS Age, CT, FIGO, TG, TS, LVSI, LNI, DI, RM, He 6
Casarin 2020 [152] Italy Retro 428 45.0 I 4.7 DFS TS, LVSI, TG, LNI 7
Wang 2020 [153] China Retro 120 59.0 I–III 3.2 OS LNI, age, FIGO, TG, TS 6
Zyla 2020 [154] Canada Retro 285 41.0 I 4.0 OS, DFS TG, CT, LVSI 6
He 2020 [155] China Retro 1,414 NA I–II 3.6 OS, DFS Age, FIGO, TS, CT, TG, DI, LVSI, PI, RM, LNI 7
Zeng 2020 [156] China Retro 251 46.0 I–III 3.9 OS, DFS FIGO, LNI 6
Liu 2020 [157] China Retro 73 NA I–II 5.7 OS Age, CT, FIGO, TG, TS, SCC 5
Kim 2020 [158] Korea Retro 47 45.0 I–II 2.4 OS, DFS FIGO, SCC, DI, RM, PI, LNI, LVSI 5
Anfinan 2020 [159] Saudi Arabia Retro 190 54.2 I–IV 3.1 OS FIGO, TG, PI 6
Lee 2020 [160] Korea Retro 125 53.7 II–III 4.2 OS, DFS Age, CT, TS, FIGO, LNI, SCC, NLR 5
Zong 2020 [161] China Retro 384 46.3 I–II 3.6 OS, DFS Age, FIGO, TG, TS, PI, LVSI, DI, RM 6
Aslan 2020 [162] Turkey Retro 185 50.0 III 3.8 OS, DFS Age, CT, DI, PI, TS, LVSI, RM, FIGO 7
Gülseren 2020 [163] Turkey Retro 194 NA I–II 5.0 DFS FIGO, TS, PI, LVSI 6
Kim 2021 [164] Korea Retro 55 52.6 I–II 4.5 DFS Age, FIGO, PI, RM 7
Okadome 2021 [165] Japan Retro 82 NA II 5.8 DFS CT, LNI, TS 6
Buda 2021 [166] Italy Retro 573 45.5 I–II 3.8 DFS Age, CT, FIGO, LVSI 6
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CT – cell type; DI – depth of invasion; He – hemoglobin; Retro – retrospective; Pro – prospective; PI – parametrial invasion; Le – leukocytosis; LVSI – lymph vascular space invasion; LNI – lymph node involvement; Ly – lymphocyte; RM – resection margin; SCC – squamous cell carcinoma antigen; TG – tumor grade; Th – thrombocytosis; TS – tumor size; TV – tumor volume; NA – not available; NLR – neutrophil/lymphocyte ratio.

Characteristics of the Eligible Studies

Of 140 included studies, 7 were designed as prospective cohorts, 132 as retrospective cohorts, and the remaining 1 study had both prospective and retrospective design. The sample size of the included studies ranged from 38 to 3797, and a total of 47 965 patients were involved. Forty-seven studies were conducted in Western countries and the remaining 93 studies were performed in Eastern countries. In addition, 106 and 99 studies reported the prognostic significance of clinicopathological characteristics, influencing OS and EFS of CC patients, respectively. Moreover, 41 studies were of medium quality (7 stars), and a total of 99 studies were of low quality (6 stars (69 studies) versus 5 stars (30 studies).

Overall Survival

The summary results for the prognostic factors on OS in CC patients are shown in Figure 2. The pooled results found older patients (HR: 1.10; 95% CI: 1.00–1.20; P=0.040), cell types other than squamous type (HR: 1.64; 95% CI: 1.47–1.83; P<0.001), deep depth of tumor invasion (HR: 1.92; 95% CI: 1.53–2.40; P<0.001), high FIGO stage (HR: 2.00; 95% CI: 1.76–2.28; P<0.001), low hemoglobin level (HR: 1.84; 95% CI: 1.36–2.50; P<0.001), high histological grade (HR: 1.52; 95% CI: 1.27–1.83; P<0.001), leukocytosis (HR: 2.21; 95% CI: 1.55–3.15; P<0.001), LNI (HR: 2.59; 95% CI: 2.30–2.92; P<0.001), LVSI (HR: 2.09; 95% CI: 1.75–2.49; P<0.001), high NLR (HR: 1.69; 95% CI: 1.36–2.11; P<0.001), parametrial invasion (HR: 2.18; 95% CI: 1.84–2.59; P<0.001), high PLR (HR: 1.98; 95% CI: 1.45–2.71; P<0.001), positive resection margin (HR: 1.97; 95% CI: 1.45–2.69; P<0.001), high SCCA level (HR: 1.65; 95% CI: 1.28–2.15; P<0.001), thrombocytosis (HR: 1.69; 95% CI: 1.32–2.17; P<0.001), large tumor volume (HR: 2.87; 95% CI: 2.03–4.04; P<0.001), high tumor grade (HR: 1.74; 95% CI: 1.24–2.43; P=0.001), and large tumor size (HR: 1.81; 95% CI: 1.59–2.07; P<0.001) were associated with shorter OS. There was significant heterogeneity for age, cell type, depth of tumor invasion, FIGO stage, hemoglobin, histological grade, leukocytosis, LNI, LVSI, NLR, parametrial invasion, resection margin, tumor grade, and tumor size. The pooled conclusions were stability for OS related to cell type, depth of tumor invasion, FIGO stage, hemoglobin level, histological grade, leukocytosis, LNI, LVSI, NLR, parametrial invasion, PLR, resection margin, SCCA level, tumor grade, and tumor size (data not shown).

Figure 2.

Figure 2

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The results of the meta-analysis of the prognostic factors influencing OS.

Subgroup analysis indicated the statistically significant prognostic significance of age in OS of patients with FIGO stages I–II CC or studies with low quality; cell type did not affect OS of patients with FIGO stages III–IV CC; depth of tumor invasion did not influence OS of patients with FIGO stages III–IV or I–IV CC; high FIGO stage did not influence OS of patients with FIGO stages III–IV CC; hemoglobin level did not influence OS of patients with FIGO stages I–II or III–IV CC; LVSI was not associated with OS in patients with FIGO stages III–IV CC; parametrial invasion did not affect OS of patients with FIGO stages III–IV CC; high PLR was not associated with OS of patients with FIGO stages I–IV CC, studies conducted in the Western countries or studies with high quality; positive resection margin did not influence OS of patients with FIGO stages III–IV CC; high SCCA level was not associated with OS of patients with FIGO stages III–IV CC, according to the results of pooled analyses conducted in the Western countries, and cutoff value ≥10; high tumor grade was not associated with OS of patients with FIGO stages I–IV CC, according to the pooled analyses conducted in the Western countries, or studies with high quality; and tumor size did not influence OS of patients with FIGO stages III–IV CC (Table 2).

Table 2.

Subgroup analysis for overall survival and event-free survival based on countries, FIGO stage, and cutoff value.

Prognostic factors Outcome Variables Subgroups HR and 95% CI P value I2 (%) Q statistic P value between subgroups
Age OS Countries Eastern 1.11 (1.00–1.23) 0.052 61.8 <0.001 0.703
Western 1.08 (0.86–1.36) 0.489 72.0 <0.001
FIGO stage I–II 1.23 (1.10–1.38) <0.001 56.2 <0.001 0.070
III–IV 1.13 (0.76–1.69) 0.539 0.0 0.719
Both 0.94 (0.79–1.13) 0.524 72.7 <0.001
Cutoff value ≥50.0 1.09 (0.97–1.23) 0.162 68.2 <0.001 0.592
<50.0 1.13 (0.96–1.33) 0.140 58.4 <0.001
Study quality High 1.03 (0.86–1.24) 0.723 71.9 <0.001 0.206
Low 1.15 (1.03–1.28) 0.016 59.8 <0.001
EFS Countries Eastern 1.19 (1.02–1.38) 0.024 67.4 <0.001 0.082
Western 1.40 (0.99–1.98) 0.061 67.5 0.002
FIGO stage I–II 1.31 (1.13–1.52) <0.001 56.3 <0.001 <0.001
III–IV 0.91 (0.59–1.40) 0.666 – –
Both 1.03 (0.76–1.39) 0.864 77.7 <0.001
Cutoff value ≥50.0 1.23 (1.04–1.46) 0.016 70.1 <0.001 0.022
<50.0 1.20 (0.96–1.51) 0.116 59.0 0.001
Study quality High 0.90 (0.76–1.08) 0.251 65.2 <0.001 <0.001
Low 1.49 (1.29–1.73) <0.001 37.6 0.019
Cell type OS Countries Eastern 1.74 (1.52–1.98) <0.001 39.9 0.007 0.047
Western 1.44 (1.20–1.73) <0.001 18.6 0.231
FIGO stage I–II 1.65 (1.43–1.91) <0.001 24.2 0.120 0.963
III–IV 1.58 (0.89–2.78) 0.115 0.0 0.521
Both 1.63 (1.36–1.95) <0.001 51.3 0.002
Study quality High 1.79 (1.53–2.09) <0.001 42.6 0.015 0.049
Low 1.50 (1.29–1.74) <0.001 26.5 0.090
EFS Countries Eastern 1.68 (1.43–1.97) <0.001 62.9 <0.001 0.008
Western 1.50 (1.18–1.91) 0.001 58.8 0.001
FIGO stage I–II 1.56 (1.31–1.86) <0.001 65.2 <0.001 0.490
III–IV 2.33 (1.38–3.94) 0.002 – –
Both 1.71 (1.37–2.13) <0.001 59.8 0.001
Study quality High 1.88 (1.57–2.24) <0.001 67.4 <0.001 0.004
Low 1.43 (1.17–1.74) <0.001 56.7 <0.001
Depth of invasion OS Countries Eastern 2.09 (1.66–2.63) <0.001 59.1 <0.001 0.024
Western 1.11 (0.52–2.38) 0.790 75.3 0.003
FIGO stage I–II 2.09 (1.65–2.63) <0.001 62.1 <0.001 0.015
III–IV 0.89 (0.42–1.89) 0.761 – –
Both 1.01 (0.43–2.37) 0.979 58.9 0.088
Cutoff value ≥1/2 2.02 (1.59–2.57) <0.001 37.2 0.053 0.782
<1/2 1.73 (1.15–2.61) 0.009 77.1 <0.001
Study quality High 1.75 (1.20–2.55) 0.004 67.5 0.001 0.680
Low 2.02 (1.51–2.40) <0.001 62.6 <0.001
EFS Countries Eastern 1.83 (1.60–2.09) <0.001 28.1 0.070 0.010
Western 1.29 (0.75–2.22) 0.359 80.7 <0.001
FIGO stage I–II 1.77 (1.52–2.06) <0.001 51.6 <0.001 0.054
III–IV 0.93 (0.51–1.71) 0.815 – –
Both 0.86 (0.32–2.31) 0.765 – –
Cutoff value ≥1/2 1.67 (1.39–2.00) <0.001 43.8 0.019 0.549
<1/2 1.77 (1.37–2.29) <0.001 60.5 <0.001
Study quality High 1.64 (1.23–2.18) 0.001 69.1 <0.001 0.596
Low 1.77 (1.49–2.09) <0.001 34.6 0.047
FIGO stage OS Countries Eastern 1.86 (1.62–2.14) <0.001 84.1 <0.001 <0.001
Western 2.36 (1.73–3.21) <0.001 85.9 <0.001
FIGO stage I–II 1.60 (1.41–1.82) <0.001 73.4 <0.001 <0.001
III–IV 1.47 (0.85–2.54) 0.168 – –
Both 2.51 (2.04–3.09) <0.001 81.7 <0.001
Cutoff value IA or IB 1.92 (1.65–2.23) <0.001 87.6 <0.001 <0.001
II–III 2.24 (1.78–2.81) <0.001 64.9 <0.001
Study quality High 2.40 (1.87–3.07) <0.001 86.9 <0.001 <0.001
Low 1.80 (1.57–2.06) <0.001 78.9 <0.001
EFS Countries Eastern 1.83 (1.60–2.08) <0.001 69.1 <0.001 0.355
Western 1.97 (1.61–2.41) <0.001 62.4 <0.001
FIGO stage I–II 1.70 (1.50–1.93) <0.001 52.6 <0.001 0.001
III–IV 1.01 (0.55–1.83) 0.984 – –
Both 2.11 (1.75–2.54) <0.001 75.5 <0.001
Cutoff value IA or IB 1.80 (1.59–2.04) <0.001 68.1 <0.001 0.021
II–III 2.04 (1.65–2.52) <0.001 62.5 <0.001
Study quality High 1.70 (1.45–2.00) <0.001 73.9 <0.001 0.023
Low 1.99 (1.72–2.31) <0.001 61.3 <0.001
Hemoglobin OS Countries Eastern 1.56 (1.15–2.10) 0.004 58.1 0.019 0.001
Western 3.05 (2.01–4.64) <0.001 0.0 0.608
FIGO stage I–II 1.39 (0.99–1.95) 0.061 0.0 0.898 0.720
III–IV 1.81 (0.90–3.64) 0.097 - -
Both 2.07 (1.34–3.19) 0.001 75.7 <0.001
Cutoff value 10 1.94 (1.13–3.36) 0.017 80.2 <0.001 0.156
>10 1.77 (1.39–2.27) <0.001 0.0 0.688
Study quality High 2.01 (1.00–4.04) 0.050 88.0 <0.001 0.337
Low 1.70 (1.33–2.17) <0.001 0.0 0.740
EFS Countries Eastern 1.20 (1.07–1.34) 0.002 4.3 0.401 0.004
Western 2.25 (1.48–3.41) <0.001 0.0 0.580
FIGO stage I–II 1.58 (1.19–2.09) 0.001 0.0 0.778 0.071
III–IV – – – –
Both 1.24 (1.03–1.50) 0.022 53.6 0.044
Cutoff value 10 1.50 (1.11–2.04) 0.009 58.9 0.023 0.248
>10 1.19 (1.04–1.35) 0.010 0.0 0.733
Study quality High 1.30 (0.86–1.96) 0.216 67.5 0.026 0.718
Low 1.29 (1.12–1.50) 0.001 18.5 0.284
Histological grade OS Countries Eastern 1.56 (1.24–1.96) <0.001 56.3 0.004 0.460
Western 1.48 (1.08–2.02) 0.014 55.0 0.011
FIGO stage I–II 1.44 (1.19–1.74) <0.001 41.6 0.030 0.414
III–IV – – – –
Both 1.75 (1.13–2.72) 0.012 72.6 0.001
Cutoff value 1 1.52 (1.20–1.92) 0.001 61.8 <0.001 0.424
2 1.56 (1.17–2.07) 0.002 32.6 0.157
Study quality High 1.43 (1.16–1.76) 0.001 29.1 0.160 0.839
Low 1.62 (1.20–2.19) 0.001 66.2 <0.001
EFS Countries Eastern 1.47 (1.09–1.97) 0.011 73.4 <0.001 0.377
Western 1.38 (1.07–1.78) 0.013 44.0 0.051
FIGO stage I–II 1.49 (1.17–1.89) 0.001 66.7 <0.001 0.340
III–IV – – – –
Both 1.24 (0.99–1.57) 0.066 0.0 0.517
Cutoff value 1 1.47 (1.13–1.90) 0.004 72.5 <0.001 0.746
2 1.41 (1.15–1.73) 0.001 0.0 0.447
Study quality High 1.43 (1.12–1.84) 0.005 64.5 0.001 0.308
Low 1.45 (1.05–2.01) 0.025 58.7 0.013
Leukocytosis OS Countries Eastern 2.20 (1.48–3.26) <0.001 75.2 0.001 0.726
Western 2.46 (1.15–5.26) 0.020 - -
FIGO stage I–II 1.55 (1.16–2.05) 0.003 0.0 0.623 0.013
III–IV 3.04 (1.52–6.07) 0.002 - -
Both 2.66 (1.53–4.64) 0.001 73.7 0.010
Cutoff value ≥10000 2.05 (1.25–3.35) 0.004 50.6 0.132 0.242
<10000 2.35 (1.39–4.00) 0.002 79.8 0.002
Study quality High 1.74 (1.18–2.56) 0.005 9.6 0.293 0.148
Low 2.41 (1.51–3.85) <0.001 76.6 0.002
EFS Countries Eastern 2.08 (1.25–3.45) 0.005 69.6 0.011 –
Western – – – –
FIGO stage I–II 1.66 (0.52–5.26) 0.389 – – 0.642
III–IV – – – –
Both 2.14 (1.20–3.81) 0.010 76.8 0.005
Cutoff value ≥10000 1.63 (0.66–4.05) 0.290 0.0 0.964 0.526
<10000 2.22 (1.16–4.24) 0.016 84.3 0.002
Study quality High 2.10 (1.62–2.74) <0.001 – – 0.685
Low 2.00 (0.86–4.65) 0.109 76.9 0.005
LNI OS Countries Eastern 2.49 (2.17–2.85) <0.001 71.4 <0.001 0.007
Western 2.90 (2.29–3.67) <0.001 60.5 <0.001
FIGO stage I–II 2.97 (2.57–3.43) <0.001 65.8 <0.001 0.001
III–IV – – – –
Both 2.04 (1.66–2.51) <0.001 72.3 <0.001
Study quality High 2.52 (2.08–3.04) <0.001 68.5 <0.001 0.639
Low 2.64 (2.26–3.09) <0.001 70.7 <0.001
EFS Countries Eastern 2.37 (2.03–2.77) <0.001 81.0 <0.001 0.001
Western 2.18 (1.75–2.72) <0.001 61.6 <0.001
FIGO stage I–II 2.54 (2.14–3.01) <0.001 81.8 <0.001 0.998
III–IV – – – –
Both 1.89 (1.57–2.26) <0.001 61.5 <0.001
Study quality High 2.16 (1.73–2.70) <0.001 87.0 <0.001 <0.001
Low 2.40 (2.10–2.75) <0.001 51.3 <0.001
LVSI OS Countries Eastern 1.99 (1.64–2.43) <0.001 63.2 <0.001 0.036
Western 2.49 (1.72–3.60) <0.001 36.3 0.100
FIGO stage I–II 2.08 (1.70–2.55) <0.001 64.6 <0.001 0.539
III–IV 2.10 (0.32–13.68) 0.438 – –
Both 2.20 (1.66–2.90) <0.001 0.0 0.976
Study quality High 1.78 (1.41–2.24) <0.001 47.4 0.029 0.046
Low 2.30 (1.80–2.94) <0.001 62.0 <0.001
EFS Countries Eastern 1.87 (1.62–2.16) <0.001 48.0 0.001 <0.001
Western 1.80 (1.33–2.46) <0.001 80.5 <0.001
FIGO stage I–II 1.92 (1.68–2.18) <0.001 51.1 <0.001 <0.001
III–IV 0.94 (0.36–2.44) 0.899 – –
Both 1.02 (0.95–1.09) 0.572 – –
Study quality High 1.77 (1.34–2.32) <0.001 85.6 <0.001 <0.001
Low 1.91 (1.63–2.23) <0.001 43.0 0.004
NLR OS Countries Eastern 1.48 (1.23–1.79) <0.001 52.9 0.038 0.001
Western 2.50 (1.39–4.50) 0.002 50.5 0.155
FIGO stage I–II 1.78 (1.37–2.31) <0.001 0.0 0.476 0.004
III–IV - – – –
Both 1.62 (1.22–2.14) 0.001 72.7 0.003
Cutoff value ≥3.0 2.40 (1.75–3.28) <0.001 0.0 0.494 <0.001
<3.0 1.35 (1.15–1.59) <0.001 41.1 0.131
Study quality High 1.58 (1.23–2.03) <0.001 75.7 0.001 0.005
Low 2.04 (1.43–2.92) <0.001 0.0 0.926
EFS Countries Eastern 1.56 (1.23–1.98) <0.001 76.6 <0.001 <0.001
Western 3.58 (2.11–6.08) <0.001 – –
FIGO stage I–II 1.99 (1.51–2.63) <0.001 0.0 0.816 <0.001
III–IV - – – –
Both 1.61 (1.17–2.21) 0.003 86.1 <0.001
Cutoff value ≥3.0 2.12 (1.28–3.52) 0.004 58.4 0.065 <0.001
< 3.0 1.51 (1.16–1.98) 0.002 81.7 <0.001
Study quality High 1.65 (1.16–2.36) 0.006 85.8 <0.001 <0.001
Low 1.85 (1.24–2.78) 0.003 60.6 0.038
Parametrial invasion OS Countries Eastern 2.16 (1.81–2.58) <0.001 31.7 0.060 0.828
Western 2.26 (1.44–3.55) <0.001 67.5 0.001
FIGO stage I–II 2.15 (1.81–2.55) <0.001 31.4 0.053 0.024
III–IV 1.11 (0.53–2.32) 0.782 – –
Both 2.26 (1.31–3.89) 0.003 68.9 0.007
Study quality High 1.90 (1.36–2.66) <0.001 66.1 0.001 0.050
Low 2.36 (1.96–2.64) <0.001 22.9 0.146
EFS Countries Eastern 1.89 (1.63–2.21) <0.001 37.6 0.019 0.948
Western 2.03 (1.66–2.21) <0.001 58.0 0.015
FIGO stage I–II 1.96 (1.68–2.28) <0.001 42.7 0.005 0.153
III–IV 3.70 (1.14–11.96) 0.029 – –
Both 1.48 (1.01–2.15) 0.044 24.9 0.262
Study quality High 1.54 (1.32–1.80) <0.001 12.1 0.321 <0.001
Low 2.23 (1.86–2.69) <0.001 32.7 0.056
PLR OS Countries Eastern 2.20 (1.62–3.00) <0.001 0.0 0.531 0.101
Western 1.54 (0.73–3.25) 0.260 69.8 0.069
FIGO stage I–II 2.10 (1.51–2.91) <0.001 0.0 0.486 0.342
III–IV – – – –
Both 1.86 (0.97–3.59) 0.062 65.6 0.055
Cutoff value ≥150 2.59 (1.68–3.99) <0.001 0.0 0.862 0.081
<150 1.72 (1.12–2.65) 0.014 48.4 0.121
Study quality High 1.55 (0.98–2.43) 0.059 45.1 0.162 0.033
Low 2.54 (1.76–3.66) <0.001 0.0 0.805
EFS Countries Eastern 2.47 (1.80–3.38) <0.001 0.0 0.914 0.004
Western 1.01 (0.60–1.70) 0.973 – –
FIGO stage I–II 2.44 (1.71–3.48) <0.001 0.0 0.779 0.058
III–IV – – – –
Both 1.58 (0.63–3.95) 0.333 78.8 0.030
Cutoff value ≥150 2.59 (1.58–4.23) <0.001 0.0 0.992 0.174
<150 1.82 (0.96–3.46) 0.069 71.3 0.030
Study quality High 1.56 (0.62–3.93) 0.343 76.7 0.038 0.045
Low 2.44 (1.72–3.46) <0.001 0.0 0.779
Resection margin OS Countries Eastern 1.88 (1.29–2.75) 0.001 65.7 0.002 0.268
Western 2.22 (1.25–3.95) 0.006 44.1 0.111
FIGO stage I–II 1.89 (1.36–2.62) <0.001 57.3 0.004 0.050
III–IV 1.55 (0.86–2.81) 0.148 – –
Both 5.49 (2.09–14.41) 0.001 – –
Study quality High 2.13 (1.24–3.66) 0.006 74.6 <0.001 0.569
Low 1.75 (1.27–2.40) 0.001 18.3 0.285
EFS Countries Eastern 2.16 (1.56–2.99) <0.001 52.2 0.006 0.129
Western 1.69 (1.20–2.37) 0.003 39.3 0.106
FIGO stage I–II 1.86 (1.43–2.43) <0.001 45.2 0.012 0.005
III–IV 1.71 (1.20–2.43) 0.003 0.0 0.925
Both 5.62 (2.78–11.37) <0.001 0.0 0.795
Study quality High 1.80 (1.33–2.45) <0.001 53.3 0.015 0.218
Low 2.26 (1.53–3.33) <0.001 45.7 0.032
SCC OS Countries Eastern 1.72 (1.26–2.35) 0.001 42.0 0.078 0.884
Western 1.50 (0.92–2.45) 0.105 – –
FIGO stage I–II 1.81 (1.22–2.68) 0.003 0.0 0.737 0.259
III–IV 1.00 (0.55–1.82) 0.992 – –
Both 1.97 (1.25–3.10) 0.003 63.1 0.028
Cutoff value ≥10 1.39 (0.76–2.53) 0.288 20.4 0.285 0.654
<10 1.77 (1.29–2.42) <0.001 45.4 0.076
Study quality High 2.61 (1.42–4.83) 0.002 37.0 0.204 0.019
Low 1.36 (1.15–1.60) <0.001 0.0 0.440
EFS Countries Eastern 1.80 (1.33–2.45) <0.001 43.7 0.087 –
Western – – – –
FIGO stage I–II 1.17 (0.61–2.22) 0.637 34.4 0.218 0.079
III–IV – – – –
Both 2.08 (1.51–2.87) <0.001 36.6 0.177
Cutoff value ≥10 1.63 (0.56–4.76) 0.370 77.4 0.035 0.954
<10 1.83 (1.33–2.53) <0.001 37.6 0.156
Study quality High 1.70 (1.14–2.56) 0.010 52.4 0.122 0.469
Low 1.86 (1.12–3.11) 0.017 48.2 0.102
Tumor grade OS Countries Eastern 2.00 (1.37–2.93) <0.001 61.5 0.016 0.007
Western 1.07 (0.78–1.45) 0.678 0.0 0.899
FIGO stage I–II 2.00 (1.37–2.93) <0.001 61.5 0.016 0.007
III–IV – – – –
Both 1.07 (0.78–1.45) 0.678 0.0 0.899
Study quality High 1.67 (0.90–3.10) 0.101 – – 0.721
Low 1.76 (1.21–2.57) 0.003 69.4 0.002
EFS Countries Eastern 1.39 (1.14–1.71) 0.001 39.2 0.130 0.480
Western 1.16 (0.60–2.26) 0.661 11.6 0.288
FIGO stage I–II 1.41 (1.17–1.70) <0.001 30.3 0.186 0.226
III–IV – – – –
Both 0.89 (0.41–1.94) 0.769 – –
Study quality High 1.35 (0.96–1.89) 0.084 54.1 0.113 0.754
Low 1.38 (1.05–1.82) 0.021 29.1 0.217
Tumor size OS Countries Eastern 1.76 (1.52–2.05) <0.001 71.7 <0.001 0.004
Western 1.95 (1.51–2.53) <0.001 59.9 0.001
FIGO stage I–II 1.66 (1.41–1.97) <0.001 70.6 <0.001 <0.001
III–IV 1.09 (0.55–2.15) 0.811 45.3 0.176
Both 2.17 (1.78–2.65) <0.001 59.1 <0.001
Cutoff value ≥4.0 cm 1.72 (1.48–2.00) <0.001 69.6 <0.001 <0.001
<4.0 cm 2.09 (1.61–2.70) <0.001 64.8 <0.001
Study quality High 1.87 (1.52–2.31) <0.001 66.1 <0.001 0.010
Low 1.78 (1.51–2.11) <0.001 70.7 <0.001
EFS Countries Eastern 1.70 (1.46–1.98) <0.001 77.8 <0.001 <0.001
Western 1.67 (1.25–2.22) 0.001 74.4 <0.001
FIGO stage I–II 1.67 (1.45–1.93) <0.001 66.9 <0.001 <0.001
III–IV 1.59 (0.89–2.83) 0.115 – –
Both 1.75 (1.34–2.28) <0.001 86.1 <0.001
Cutoff value ≥4.0 cm 1.66 (1.39–1.98) <0.001 78.5 <0.001 0.062
<4.0 cm 1.76 (1.43–2.17) <0.001 77.1 <0.001
Study quality High 1.48 (1.28–1.72) <0.001 68.3 <0.001 0.053
Low 1.90 (1.54–2.35) <0.001 81.3 <0.001
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There was significant publication bias for the prognostic significance of FIGO stage (P (Egger’s test) <0.001; P (Begg’s test)=0.749), hemoglobin level (P (Egger’s test)=0.013; P (Begg’s test)=0.119), histological grade (P (Egger’s test)=0.044; P (Begg’s test)=0.024), LVSI (P (Egger’s test)=0.026; P (Begg’s test)=0.056), NLR (P (Egger’s test)=0.001; P (Begg’s test)=0.074), PLR (P (Egger’s test)=0.020; P (Begg’s test)=0.007), tumor grade (P (Egger’s test)=0.031; P (Begg’s test)=0.048), and tumor size (P (Egger’s test)=0.006; P (Begg’s test)=0.950) in OS (Table 3). The pooled conclusion for OS were not changed after adjustment for publication bias by using the trim and fill method.

Table 3.

Publication bias for clinicopathological factors.

Factors OS EFS
Egger Begg Egger Begg
Age 0.261 0.298 <0.001 0.010
Cell type 0.052 0.114 0.083 0.057
Depth of invasion 0.641 0.700 0.624 0.408
FIGO stage <0.001 0.749 0.016 0.061
Hemoglobin 0.013 0.119 0.026 0.024
Histological grade 0.044 0.024 0.186 0.063
Leukocytosis 0.624 0.368 0.831 0.806
LNI 0.127 0.603 <0.001 0.460
LVSI 0.026 0.056 <0.001 0.273
NLR 0.001 0.074 0.006 0.210
Parametrial invasion 0.640 0.948 0.566 0.972
PLR 0.020 0.007 0.388 0.221
Resection margin 0.101 0.260 0.087 0.378
SCC 0.139 0.533 0.430 0.536
Tumor grade 0.031 0.048 0.568 1.000
Tumor size 0.006 0.950 <0.001 0.082
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Event-Free Survival

The summary results for the prognostic factors on EFS in CC patients are shown in Figure 3. The pooled analyses indicated that older patients (HR: 1.22; 95% CI: 1.06–1.40; P=0.004), cell types other than squamous type (HR: 1.62; 95% CI: 1.42–1.86; P<0.001), deep depth of tumor invasion (HR: 1.72; 95% CI: 1.48–2.00; P<0.001), high FIGO stage (HR: 1.87; 95% CI: 1.67–2.08; P<0.001), low hemoglobin level (HR: 1.31; 95% CI: 1.12–1.53; P=0.001), high histological grade (HR: 1.43; 95% CI: 1.18–1.74; P<0.001), leukocytosis (HR: 2.08; 95% CI: 1.25–3.45; P=0.005), LNI (HR: 2.32; 95% CI: 2.03–2.64; P<0.001), LVSI (HR: 1.87; 95% CI: 1.60–2.18; P<0.001), high NLR (HR: 1.73; 95% CI: 1.33–2.25; P<0.001), parametrial invasion (HR: 1.91; 95% CI: 1.66–2.21; P<0.001), high PLR (HR: 2.05; 95% CI: 1.35–3.10; P=0.001), positive resection margin (HR: 1.99; 95% CI: 1.56–2.52; P<0.001), high SCCA level (HR: 1.80; 95% CI: 1.33–2.45; P<0.001), thrombocytosis (HR: 1.47; 95% CI: 1.08–1.98; P=0.013), large tumor volume (HR: 1.86; 95% CI: 1.40–2.47; P<0.001), high tumor grade (HR: 1.37; 95% CI: 1.14–1.66; P=0.001), and large tumor size (HR: 1.68; 95% CI: 1.48–1.90; P<0.001) were associated with shorter EFS. There was significant heterogeneity for age, cell type, depth of tumor invasion, FIGO stage, hemoglobin, histological grade, leukocytosis, LNI, LVSI, NLR, parametrial invasion, PLR, resection margin, SCCA level, and tumor size. The pooled conclusions were stability for EFS related to age, cell type, depth of tumor invasion, FIGO stage, hemoglobin level, histological grade, LNI, LVSI, NLR, parametrial invasion, PLR, resection margin, SCCA level, tumor grade, and tumor size (Data not shown).

Figure 3.

Figure 3

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The results of the meta-analysis of the prognostic factors influencing EFS.

Subgroup analysis indicated the statistically significant prognostic significance of age in EFS was observed for studies performed in Eastern countries, patients with FIGO stages I–II CC, the cutoff value of age was ≥50.0, and studies with low quality; depth of tumor invasion did not influence EFS of patients with FIGO stages III–IV or I–IV CC; high FIGO stage did not influence EFS of patients with FIGO stages III–IV CC; EFS were not affected by hemoglobin when pooled studies with high quality; histological grade did not influence EFS of patients with FIGO stages I–IV CC; leukocytosis did not impact EFS of patients with FIGO stages I–II CC, and cutoff value ≥10 000, or studies with low quality; LVSI was not associated with EFS in patients with FIGO stages III–IV or I–IV CC; PLR did not influence EFS of patients with FIGO stages I–IV CC, studies conducted in the Western countries, cutoff value <150, or studies with high quality; high SCCA level did not affect EFS of patients with FIGO stages I–II CC, or cutoff value ≥10; high tumor grade was not associated with EFS of patients with FIGO stages I–IV CC, according to the pooled analyses conducted in the Western countries, or studies with high quality; and tumor size did not influence EFS of patients with FIGO stages III–IV CC (Table 2).

There was significant publication bias for the prognostic significance of age (P (Egger’s test) <0.001; P (Begg’s test)=0.010), FIGO stage (P (Egger’s test)=0.016; P (Begg’s test)=0.061), hemoglobin level (P (Egger’s test)=0.026; P (Begg’s test)=0.024), LNI (P (Egger’s test) <0.001; P (Begg’s test)=0.460), LVSI (P (Egger’s test) <0.001; P (Begg’s test)=0.273), NLR (P (Egger’s test)=0.006; P (Begg’s test)=0.210), and tumor size (P (Egger’s test) <0.001; P (Begg’s test)=0.082) in EFS (Table 3). The pooled conclusions for EFS were not altered after adjusting for potential publication bias.

Discussion

The results of this study showed that the potential risk factors for OS and EFS were age, cell type, depth of tumor invasion, FIGO stage, hemoglobin level, histological grade, leukocytosis, LNI, LVSI, NLR, parametrial invasion, PLR, resection margin, SCCA level, thrombocytosis, tumor grade, tumor size, and tumor volume. Moreover, we noted that the first author’s country of residence could affect the prognostic significance of cell type, depth of tumor invasion, FIGO stage, hemoglobin level, LNI, LVSI, NLR, tumor stage, and tumor size in OS, and the prognostic significance of cell type, depth of tumor invasion, hemoglobin level, LNI, LVSI, NLR, PLR, and tumor size in EFS was influenced by the first author’s country of residence. Furthermore, FIGO stage could affect the prognostic significance of depth of tumor invasion, leukocytosis, LNI, NLR, parametrial invasion, resection margin, tumor grade, and tumor size in OS, and the prognostic significance of age, LVSI, NLR, resection margin, and tumor size in EFS could be influenced by FIGO stage. We also found that cutoff value affected the prognostic significance of FIGO stage, NLR, and tumor size in OS, and the prognostic significance of age, FIGO stage, and NLR in EFS could be affected by cutoff value. Finally, the study quality could affect the prognostic significance of cell type, FIGO stage, LVSI, NLR, parametrial invasion, PLR, SCCA, and tumor size in OS, while the prognostic significance of age, cell type, FIGO stage, LNI, LVSI, NLR, parametrial invasion, and PLR in EFS could affect by study quality.

A previous meta-analysis of 22 studies revealed that the prognosis of CC was influenced by advanced FIGO stage, large tumor size, LNI, LVSI, parametrial invasion, depth of tumor invasion, and radiation therapy [118]. Zhang et al retrieved 20 cohort studies and found that FIGO stage, tumor size, parametrial invasion, resection margin, LNI, depth of tumor invasion, neoadjuvant chemotherapy, and adjuvant chemotherapy could affect OS of patients with CC [167]. However, other meta-analyses investigated the prognostic factors for OS, whereas those factors for EFS were not assessed. Moreover, the prognostic significance of clinicopathological factors, influencing OS and EFS of CC patients, which could be influenced by the first author’s country of origin, FIGO stage, and cutoff value, were not evaluated. We therefore conducted the present systematic review and meta-analysis to identify the prognostic significance of clinicopathological factors influencing OS and EFS of patients with CC.

Compared with previous studies, this study revealed that FIGO stage, tumor size, parametrial invasion, resection margin, LNI, LVSI, and depth of tumor invasion could affect the prognosis of CC patients, which may be related to the fact that these factors could directly reflect distant metastasis and are associated with a poor prognosis of CC patients [168–170]. Furthermore, we studied additional prognostic factors, such as age, cell type, hemoglobin level, histological grade, leukocytosis, NLR, PLR, SCCA level, thrombocytosis, tumor grade, and tumor volume. The above-mentioned results could be explained as follows: (1) The incidence of CC varies among different age-based groups, and the FIGO stage of CC also significantly differs among various age-based groups [2]; (2) Compared with squamous cell carcinoma, patients with adenocarcinoma may tend to have other extracervical spread, associating with a poor prognosis of CC patients [171]; (3) The hemoglobin level is significantly correlated to the tumor size and infiltrative phenotypes of tumors [172,173]; Moreover, the hemoglobin level may act as a surrogate marker of tumor hypoxia, which is significantly associated with resistance to radiotherapy [174]; (4) Histological grade, tumor grade, and tumor volume are significantly correlated to tumor extension and invasion, which may influence the prognosis of CC patients; (5) Leukocytosis in CC patients is associated with a poor prognosis, which may be related to a poor response to radiation therapy [100]; (6) Increased NLR is markedly associated with a large tumor size, advanced clinical stage, and positive LNI, resulting in shorter OS and EFS [15]; (7) Elevated PLR can induce inflammatory cytokines and chemokines, promoting the progression of cancer cells [175]; (8) Increased SCCA concentration can reflect the degree of cell proliferation for patients with CC [176]; and (9) Cancer treatment can induce thrombocytosis, cytokines or growth factors, receptors, and downstream effectors, playing an important role in the prognosis of CC [177].

The current meta-analysis indicated the prognostic significance of cell type, depth of tumor invasion, FIGO stage, hemoglobin level, LNI, LVSI, NLR, PLR, tumor stage, and tumor size, which significantly differed in patients studied in the Eastern and Western countries. The results were based on the diagnosis of CC patients at various FIGO stages in different countries. Moreover, the vaccination rate in the Eastern and Western countries is different, influencing the incidence and prognosis of CC. Moreover, the effects of age, depth of tumor invasion, leukocytosis, LNI, LVSI, NLR, parametrial invasion, resection margin, tumor grade, and tumor size on the prognosis of CC patients could be influenced by FIGO stage. Additionally, the effects of age, FIGO stage, NLR, and tumor size on the prognosis of CC patients could be affected by the cutoff value.

The strengths of our study include: (1) our study contained 18 clinicopathological factors, which provide relatively comprehensive prognostic factors for CC; (2) the analysis was based on a large number of included studies, and the pooled conclusions are potentially more robust than are those of any individual study; and (3) subgroup analyses were performed for prognostic factors reported by more than 5 studies, which could assess the prognostic role of clinicopathological factors on OS and EFS according to studies’ characteristics. Several shortcoming of this study should be pointed out: (1) the majority of the included studies had a retrospective design, and selection or confounder biases were therefore inevitable; (2) the noticeable changes of the cutoff values partly expanded the range of the results of subgroup analyses; (3) the heterogeneity among the included studies was not fully explained by the results of the sensitivity and subgroup analyses; (4) the treatment strategies for CC significantly differed among the included studies, which could influence the prognosis of CC patients; (5) several other outcomes should be addressed in further large-scale prospective studies, including response to chemotherapy, remission rates, hospitalization rates, and complication rates; (6) the transparency of our study was restricted because it was not registered in PROSPERO; and (7) inherent limitations of meta-analysis of previously published articles are noteworthy.

Conclusions

This study comprehensively identified the prognostic significance of clinicopathological factors and influencing OS and EFS of patients with CC, including age, cell type, depth of tumor invasion, FIGO stage, hemoglobin level, histological grade, leukocytosis, LNI, LVSI, NLR, parametrial invasion, PLR, resection margin, SCCA level, thrombocytosis, tumor grade, tumor size, and tumor volume. However, further large-scale prospective studies should be conducted to verify our findings and develop more accurate prognostic models for CC.

Abbreviations

CC

cervical cancer

CI

confidence interval

EFS

event-free survival

FIGO

International Federation of Gynecology and Obstetrics

HR

hazard ratio

LNI

lymph node involvement

LVSI

lymph-vascular space invasion

NLR

neutrophil-to-lymphocyte ratio

NOS

Newcastle-Ottawa Scale

OS

overall survival

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analysis

PLR

platelet-to-lymphocyte ratio

SCCA

squamous cell carcinoma antigen

Footnotes

Conflict of interest: None declared

Declaration of Figures’ Authenticity

All figures submitted have been created by the authors who confirm that the images are original with no duplication and have not been previously published in whole or in part.

Financial support: This study was financially supported by the Key R&D Projects in Sichuan Province (2021YFG0168)

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